Limitations to effective immunotherapy are increasingly being recognized. Specifically, a number of regulatory/ suppressive pathways have been identified that present significant barriers to the tumor antigens in cancer-bearing hosts. Amongst these, myeloid suppressor cells (MSCs) are directly associated with increasing tumor burdens and exert their inhibitory effects through the production of nitric oxide and arginase-1. In this proposal, we seek to: 1) determine the relationship between the generation of MSCs and the development of antigen-specific T cell tolerance in a T cell receptor transgenic model with specific attention to paid to the inter-relationship between MSCs and Tregs. 2) examine the role of MSCs during tumor progression in hematologic malignancies. 3) examine the role of bone marrow transplantation in MSC turnover and develop strategies to overcome MSC- mediated immunosuppression. Specifically, we will study the role of IL4Ra+ MSCs utilizing the LysMcre IL4Ra+flox mice in immunosuppression. We will also examine the role of PDE5 inhibitors such as sildenafil in abrogating MSC function and test various therapeutic conditions in an effort to maximize antitumor immunity. Lay abstract: A major barrier to effective anti-cancer immunotherapy is the ability to mount a clinically meaningful anti- tumor response. To do so, the host must be capable of overcoming the intrinsic suppressive mechanisms that limit the development of effective immune responses. One such mechanism is the generation of myeloid suppressor cells (MSCs) that increase with increasing tumor burden and inhibit immune responsiveness. To date, most of the work in this field has focused on their role in solid tumors. Here, we propose to examine the effect of MSCs in mouse models of liquid tumors- namely lymphoma. We will also attempt to determine how bone marrow transplantation impacts on MSC function and turnover. Lastly, we will attempt to develop strategies to reduce MSC function in the transplant setting through the use of Viagra and related drugs based on our recent observations that these drugs can effectively inhibit MSC function.